The objective of this proposal is to use this 5-year training grant to acquire the knowledge and skills necessary to become an independent researcher. The PI will be mentored by Dr. James Fagin who is a leading scientist in thyroid cancer biology at Memorial-Sloan Kettering Cancer Center. The purpose of this research is to explore the role of tumor-associated macrophages (TAMs) in thyroid cancer progression. Multiple lines of evidence demonstrate that tumors paradoxically alter the host anti-tumor immune response to promote tumor progression through immune-mediated tumor growth, angiogenesis, lymphangiogenesis, invasion and metastases. We have shown that in human thyroid cancers, TAMs correlate with tumor grade. In advanced stages of thyroid cancer, TAMs correlate with invasion and decreased survival. This suggests that TAMs facilitate thyroid cancer progression. Our lab has several mouse models of Braf- induced thyroid cancers, which is the most common oncogenic event in human thyroid cancers. Thyroid cancers in this model, similar to humans, are infiltrated with TAMs, and tumors progress to invasion, poorly- differentiated cancers and metastases. Our hypothesis is that TAMs facilitate thyroid cancer progression. We will test this hypothesis using several genetic approach to deplete TAMs in thyroid cancer mouse models. In preliminary data, we show that the depletion of TAMs in thyroid cancers impairs thyroid cancer initiation and progression. This may be in part through TAM-dependent tumor stromal expansion with cancer-associated fibroblasts (CAFs) and pericytes, as we will show in preliminary data. Our specific aims are to characterize the kinetics and differentiation status of TAMs in thyroid cancers and determine which chemokines are required for TAM recruitment and/or differentiation. We will examine the effects of TAMs on the recruitment, differentiation and/or proliferation of CAF progenitors from the bone-marrow and thyroid. Finally examine the effects of TAMs directly on thyroid cancer derived CAFs and pericytes. The results of these investigations will help identify potential mechanisms of thyroid cancer pathogenesis through recruitment and interactions of host immune cells. This knowledge and understanding can then be used to develop new targets for cancer therapy for patients whose disease has not responded to traditional treatments.